JP3835815B2 - Enrofloxacin injection or infusion solution - Google Patents

Description

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The present invention relates to a novel injection or infusion solution of enrofloxacin.
A solution of quinolone carboxylic acid for parenteral administration is already known from EP 67 666. These are based on the salts of the corresponding quinolone carboxylic acids with various hydroxy carboxylic acids.
A solution for injection or infusion of quinolone carboxylic acids, in particular ciprofloxacin, based on lactate with an excess of acid is known from EP 138 018.
An injectable aqueous solution of about 0.01 to 0.5% ciprofloxacin with acid added for stabilization is known from EP 214 784. In said document, lactic acid is mentioned as a particularly preferred acid.
A solution for injection based on a suspension of fine quinolone carboxylic acids is known from DE 39 02 079.
The present invention has the following composition:
a) 0.1-20% by weight of enrofloxacin, based on the total weight of the solution, in the form of a salt with polyhydroxycarboxylic acid or amino acid or mixtures thereof;
b) 0.1-5 molar excess of polyhydroxycarboxylic acid, amino acid, or mixture thereof based on enrofloxacin;
c) optionally 0.1-30% by weight of formulation adjuvant, based on the total weight of the solution;
d) Water up to 100% by weight:
To new injectable and infusible solutions.
Compared to previously known solutions of enrofuroxin for injection, the solution according to the invention has the advantage of a powerful effect that occurs rapidly. This is only indicated by the fact that high blood levels of the active substance are achieved within a short period after administration. However, the active substance is excreted more rapidly, which is a great advantage (short waiting time), especially in the treatment of animals used for food production.
Injectable and infusion solutions according to the invention preferably contain the active substance enrofloxacin in a concentration of 1 to 10%, particularly preferably 2.5 to 10% (weight percent based on the total weight of the solution).
Polyhydroxycarboxylic acids that may be mentioned are gluconic acid, galacturonic acid, glucuronic acid and lactobionic acid. These acids can take the open chain form or the lactone form. When these acids are used as lactones, the lactone ring is at least partially hydrolyzed before salt formation and complex formation with enrofloxacin occurs. Amino acids that may be mentioned are glutamic acid and aspartic acid. The polyhydroxycarboxylic acid or amino acid is present in a 0.1-5 molar excess based on the amount of enrofloxacin in the solution. The excess amount of the acid is preferably 0.2 to 2 mol, particularly preferably 0.5 to 1 mol.
The acid part present in excess is further replaced by other acids (eg hydrochloric acid, methanesulfonic acid, ethanesulfonic acid, propionic acid, succinic acid, glutaric acid, citric acid, ascorbic acid, phosphoric acid or lactic acid). obtain.
In addition to water for injection, aqueous solutions for injection can further contain ethanol, glycerol, propylene glycol, polyethylene glycol, and triethylene glycol, for example, as liquid excipients. The pH is as much as possible by using various substances such as phosphoric acid, citric acid, Tris, ascorbic acid, acetic acid, succinic acid, tartaric acid, gluconic acid, and lactic acid, and salts thereof. A range of 6.5 can be adjusted. The pH of the aqueous preparation according to the invention is 3 to 5.5, preferably 3.5 to 5. The osmolality of the aqueous suspension is 200 to 900 mOsmol / kg, preferably 260 to 390 mOsmol / kg, and NaCl, glucose, fructose, glycerol, sorbitol, mannitol, sucrose, or xylitol, or the substance thereof. This aqueous suspension can be employed under isotonic conditions by the addition of a mixture.
For example, thickeners (in one example, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and gelatin), absorbents, light stabilizers, crystallization retarders, complexing agents (in one example, among others) NaEDTA, phosphoric acid, nitric acid, acetic acid, and citric acid), antioxidants (among others, ascorbic acid, sulfite compounds, L-cysteine, thiodipropionic acid, thiolactic acid, monothioglycerol, and propyl gallate) and storage Preparation aids (among others, PHB esters, phenols and derivatives, chlorobutanol, benzyl alcohol, ethanol, butanol, butane-1,3-diol, chlorohexidine salts, benzoic acid and salts, and sorbic acid) It is also possible to further use. For example, local anesthetics such as procaine hydrochloride and lidocaine hydrochloride can optionally be added to the solution according to the invention.
Injectable or infusion solutions according to the invention can be prepared starting from enrofloxacin with the corresponding acid or starting from its hydrate.
However, it is also possible to prepare the salt directly in the solution by adding the amount of acid required for salt formation. Dissolution can be facilitated by working at temperatures between 30 ° C and 60 ° C. This solution can be prepared under nitrogen gas.
In this manner, a ready-to-use solution of the active substance in a suitable container such as an ampoule, injection vial or infusion bottle, or such a solution such as a concentrate or lyophilizate, for example. Any of the precursors suitable for this preparation can be prepared.
The container filled with the preparation may be made of glass or plastic, and the material of the container contains a substance that gives the container a special protective function (eg protection from light or oxygen). Is possible.
The preparation of solutions in the following examples can be carried out in batch vessels with or without a heat transfer jacket. When using a non-heating container, preheated water can be used if necessary.
Generally, the volume of solvent is taken into the vessel and the individual components are dissolved there, but it is also possible to add the solvent to the solid.
When acids are used in their lactone form, they are hydrolyzed to the free acid after dissolution, generally by heating or standing before the active agent is added. The temperature used there is 40-70 ° C, preferably 50-60 ° C.
The other components are then dissolved or incorporated into the preparation after stirring or before cooling with stirring. After replenishing the remaining solvent, the preparation can be sterile filtered and / or heat sterilized through a suitable bacteria retention filter.
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Claims (2)

Injection or infusion solution having the following composition:
a) 2.5 to 10% by weight based on the total weight of the solution for injection or infusion in the form of a salt with an organic acid selected from the group consisting of gluconic acid, glucuronic acid, glutamic acid, tartaric acid and mixtures thereof Enrofloxacin;
b) 0.1-5 molar excess of the organic acid based on enrofloxacin;
c) optionally from 0.1 to 30% by weight of preparation aid based on the total weight of the solution; and d) water to 100% by weight. a) 2.5 to 10% by weight based on the total weight of the solution for injection or infusion in the form of a salt with an organic acid selected from the group consisting of gluconic acid, glucuronic acid, glutamic acid, tartaric acid and mixtures thereof Enrofloxacin;
b) 0.1-5 molar excess of the organic acid based on enrofloxacin;
c) optionally 0.1 to 30% by weight of preparation aid, based on the total weight of the solution for injection or infusion; and d) water up to 100% by weight:
A method of preparing an injectable or infusible solution having the composition: wherein enrofloxacin is stirred in an aqueous solution of the organic acid, the remaining preparation adjuvants are added, and if desired, the desired concentration is adjusted. A method characterized in that it is obtained by dilution with water .